Theophylline is a naturally occurring xanthine alkaloid with potent bronchodilator properties. It is especially useful for treating bronchial asthma and is widely used to treat asthma in children. Theophylline's acceptability by patients, particularly children, is reduced because it has a very bitter taste which is difficult to mask. Children and a portion of the adult population may have difficulty in swallowing tablets and capsules and hence require dosage forms of chewable tablets or liquids. Since these latter dosage forms must have an acceptable taste, it is difficult to formulate theophylline into such oral formulations.
Aminophylline, the ethylenediamine salt of theophylline which is a commonly used form of theophylline, also has an unacceptability bitter taste.
Because theophylline and aminophylline are water soluble, 8 mg/ml and 200 mg/ml at room temperature respectively, it is difficult to mask their bitter tastes, the reason oral administration to children is difficult if not impossible.
In addition to the taste problem, orally administered aminophylline and theophylline can cause undesirable side effects, particularly gastric distress and irritation. One potential cause for this, in the case of aminophylline, is that aminophylline is rapidly hydrolyzed in the acidic environment of the stomach releasing large amounts of free theophylline and ethylenediamine very quickly.
Theophylline has a narrow therapeutic range and blood concentrations above this range can cause toxic side effects. Because of the solubility of theophylline and aminophylline, it is very difficult to control the blood concentration pattern of theophylline to keep it in the acceptable therapeutically effective range.
If administered as aminophylline, all the theophylline is released very rapidly into the stomach where it is absorbed and reaches a peak blood concentration very quickly. This peak can easily be in the toxic range since effective dosages are very close to the toxic level. This can be overcome by more frequent administrations while decreasing the dosage per administration, a generally unacceptable approach.
If administered as theophylline per se, the theophylline is abosrbed very quickly and rapidly produces peak concentrations in the bloodstream, also resulting in possible toxic effects.
Reports in the literature with a variety of theophylline derivatives show that the theophylline blood concentrations achieved in many instances are below the values required for relief of bronchospasm and even when therapeutic concentrations are obtained, they fall off extremely rapidly in the first few hours following administration of the drug. Thus repeated dosing of the patient about every three to four hours is necessary. Generally the drug is administered orally, although it can be parenterally administered. Oral administration is preferred because of the frequency of administration required and the patient's convenience.
On exposure to air aminophylline will gradually lose ethylenediamine and absorb carbon dioxide. This creates a stability problem that can be controlled by careful formulation of the dosage form and proper storage conditions.
There is a need for a storage stable theophylline compound having an acceptable taste and chemical characteristics which make available suitable therapeutic blood levels of theophylline and maintain these blood levels for a sufficient length of time to reduce or eliminate the danger of undesirable side effects.